Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrena gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as an agent for control of hypertension, congestive heart failure, and hyperaldosteronism.
The present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, glaucoma, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
Since HIV protease, like renin, is an aspartyl protease, the compounds of the instant invention can also be used to treat diseases caused by retroviruses including HTLV-I, -II, and -III.
European Application No. 184,855 covers renin-inhibitory peptides of the formula ##STR1## wherein A is an N-protecting group; R.sub.1, R.sub.3, R.sub.5 and R.sub.7 are lower alkyl or lipophilic or aromatic amino acid side chains and may be the same or different; R.sub.2, R.sub.4 and R.sub.6 are hydrogen or lower alkyl and may be the same or different; X is hydrogen, lower alkyl or --CH.sub.2 --OR.sub.8, wherein R.sub.8 is hydrogen, lower alkyl or alkaryl; and R.sub.9 is lower alkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, alkaryloxy or thioalkyl and pharmaceutically acceptable salts thereof.
European Application No. 192,544 covers peptide pepstatin analogues of the formula ##STR2## wherein R.sub.1 is COR or SO.sub.2 R.sup.1 ; R.sub.2 is optionally substituted lower alkyl, phenyl, naphthyl, cyclohexyl or pyridyl; R.sub.3 is hydrogen, lower alkenyl, phenyl, naphthyl, 3-6C cycloalkyl, monocyclic heterocyclic or substituted lower alkyl; Z.sub.1 is i-Pr, phenyl, cyclohexyl; X-Y is a dipeptide.
European Application No. 220,665 covers peptidyl, amino cycloalkyl, hydroxy alkanoic acid derivatives of the formula EQU X--Z--NR.sub.2 --CHR.sub.3 --CHOH--(CHR.sub.4).sub.n --CO--E
wherein
X=H, R.sub.1 OC.sub.m H.sub.2m CO, R.sub.1 C.sub.m H.sub.2m OCO, R.sub.1 C.sub.m H.sub.2m CO, R.sub.1 SO.sub.2, Q--C.sub.r H.sub.2r CO, H(NHCH.sub.2 CH.sub.2).sub.m NHCH.sub.2 CO or 9-fluorenyl--C.sub.m H.sub.2m OCO; PA0 Z=1-4 peptide-linked aminoacid groups selected from Abu, Ada, Ala, Arg, Asn, Bia, Cal, Dab, Gln, Gly, His, N(im)-alkyl-His, Ile, Leu, tert-Leu, Lys, Met, .alpha.-Nal, .beta.-Nal, Nbg, Nle, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val; and PA0 E=OH, OA, NH.sub.2, NHA or N(A).sub.2. PA0 A is, e.g., benzyloxycarbonyl, t-butoxycarbonyl, 1-naphthyloxyacetyl or 1-naphthylacetyl; PA0 B is, e.g., phenylalanine, 3-(1-naphthyl)alanine), tryptophan or homophenylalanine; PA0 D is, e.g., histidine, lysine or phenylalanine; PA0 E is, e.g., one of the following formulae: ##STR3## and G is e.g., --OH, --OEt, --NH.sub.2. Those compounds inhibit enzymes and can be used as pharmaceutical agents. PA0 A is, e.g., hydrogen, or R.sub.1 --, R.sub.b CO or R.sub.b SO.sub.2 --where R.sub.a and R.sub.b are e.g., alkyl, cycloalkyl, or aryl; PA0 E is ##STR4## G is --R.sup.3 or is ##STR5## wherein R.sup.1 is, e.g., alkyl; PA0 n is 0,1; PA0 R.sup.2 is, e.g., hydrogen or alkyl; PA0 R.sup.3 is OH, NH.sub.2, NHR.sub.a'.sup.3, NR.sub.a'.sup.3 N.sub.b'.sup.3, PA0 OR.sub.a.sup.3 where R.sub.b'.sup.3, and R.sub.c.sup.3 are e.g., alkyl; PA0 R.sup.4 is, e.g., hydrogen or alkyl; PA0 R.sup.6 is H or methyl; PA0 R.sup.7 is, e.g., hydrogen or alkyl; PA0 R.sup.8 is, e.g., hydrogen, methyl or cycloalkyl such that when R.sup.9 is cycloalkyl, R.sup.6 and R.sup.7 are hydrogen; PA0 R.sup.9 is, e.g., hydroxy. PA0 n is an integer from one to five; PA0 p and p'are zero or 1; PA0 g is an integer from 2 to 5; PA0 R.sub.10 is --(CH.sub.2).sub.m --R.sub.6 '; PA0 A and A' are a single bond or --(CH)--(CH.sub.2).sub.m --R.sub.6 ", and R.sub.6, R.sub.6 ', and R.sub.6 " are independently selected from hydrogen, alkyl, and aryl, and cycloalkyl, or R.sub.6 and R.sub.6 ' taken together with the atom to which they are bonded may form a ring of three to five carbons.
The compounds are useful as renin and acid protease inhibitors.
European Application 209,848 covers phosphorous-containing amino acids as inhibitors of renin and angiotensin converting enzyme of the formula EQU A--B--D--E--G
wherein
European Application 210,545 covers phosphorous-containing amino acids and dipeptide compounds of the formula EQU A--E--G
wherein
The compounds have enzyme inhibitor activity, e.g., renin inhibition or angiotensin converting enzyme inhibition.
U.S. Pat. No. 4,845,079 covers peptidylaminodiols of the formula ##STR6## wherein A is a substituent; W is C.dbd.O or CHOH; U is CH.sub.2 or NR.sub.2, provided when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoly)methyl, .alpha.,.alpha.-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.2 is hydrogen or loweralkyl; R.sub.3 is loweralkyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is loweralkyl, cycloalky-methyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or loweralkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R.sub.5 and R.sub.7 are both hydrogen and R.sub.8 and R.sub.9 are OH, the carbon bearing R.sub.5 is of the "R" configuration and the carbon bearing R.sub.6 is of the "S" configuration; or pharmaceutically acceptable salts or esters thereof as renin inhibitors for the treatment of hypertension.
British Patent Application 2,212,804 covers N-heterocyclic alcohol derivatives of the formula ##STR7## are disclosed. These compounds are inhibitors of renin and therefore useful as cardiovascular agents.
The symbols have the following definitions: ##STR8##
R.sub.1 is fully saturated, partially saturated, or unsaturated monocyclic N-heterocyclic ring of five or six atoms containing at least one N atom or a bicyclic ring in which said N-heterocyclic ring is fused to a benzene ring.
R.sub.3, R.sub.4, and R.sub.6 are independently selected from hydrogen or optionally substituted alkyl, m, m', and m" are zero or an integer from 1 to 5;